Superoxide dismutase reaction mechanisms

R6. Rotilio, G., Morpurgo, L., Calabrese, L., and Mondovi, B On the mechanism of superoxide dismutase reaction of the bovine enzyme with hydrogen peroxide and ferrocyanide. Biochim. Biophys. Acta 302, 229-235 (1973). 

One major problem in this area is that a satisfactory chemical explanation for the purported toxicity of superoxide has never been found, despite much indirect evidence from in vitro experiments that the presence of superoxide can lead to undesirable oxidation of various cell components and that such oxidation can be inhibited by superoxide dismutase. The mechanism most commonly proposed is production of hydroxyl radicals via Reactions (5.28) to (5.30) with Red =02, which is referred to as the Metal-Catalyzed Haber-Weiss Re-... 

As described in Section 15.7, enzymes are the catalysts of biological reactions. Without enzymes, most of the reactions that occur in a cell would be imperceptibly slow. Cations of transition metals play essential roles in the mechanisms of many enzyme-catalyzed reactions. Here we introduce just one representative example, superoxide dismutase. 

J.M. McCord and I. Fridovich, Utility of superoxide dismutase in studying free radical reactions. II. Mechanism of the mediation of cytochrome c reduction by a variety of electron carriers. J. Biol. Chem. 245,1374-1377 (1970). 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

The transfer of a quadridentate N2S2-donor ligand from M2+ (M = Cr, Mn, Fe, Co or Ni) to Cu2+ (271), already mentioned in Section V.A.l, has a formal connection with an investigation of the mechanism of copper delivery to metalloproteins, such as copper zinc superoxide dismutase. Both are ligand exchange reactions of the type ML + CuL ML + CuL (300). 

On the other hand, several ROS are highly cytotoxic. Consequently, eukaryotic cells have developed an elaborate arsenal of antioxidant mechanisms to neutrahze their deleterious effects (enzymes such as superoxide dismutases, catalases, glutathione peroxidases, thioredoxin inhibitors of free-radical chain reaction such as tocopherol, carotenoids, ascorbic acid chelating proteins such as lactoferrin and transferrin). It can be postulated that ROS may induce an oxidative stress leading to cell death when the level of intracellular ROS exceeds an undefined threshold. Indeed, numerous observations have shown that ROS are mediators of cell death, particularly apoptosis (Maziere et al., 2000 Girotti, 1998 Kinscherf et al., 1998 Suzuki et al., 1997 Buttke and Sanstrom, 1994 Albina et al., 1993). 

Rieke proteins, 47 337, 347-355 superoxide dismutases and, 45 129 Photosynthetic bacteria, 2[4Fe-4S] and [4Fe-4S] [3Fe-4S] ferredoxins, 38 255-257 Photosystem 1, 38 303-304 Pa/Fb proteins, 38 262-263 reaction center X proteins, single [4Fe-4S] ferredoxins cluster bridging two subunits, 38 251-252 Photosystem II, 46 328 interatomic separations, 33 228 mechanisms for water oxidation, 33 244-247... 

Guanine is the most easily oxidizable natural nucleic acid base [8] and many oxidants can selectively oxidize guanine in DNA [95]. Here, we focus on the site-selective oxidation of guanine by the carbonate radical anion, COs , one of the important emerging free radicals in biological systems [96]. The mechanism of COs generation in vivo can involve one-electron oxidation of HCOs at the active site of copper-zinc superoxide dismutase [97, 98], and homolysis of the nitrosoperoxycarbonate anion (0N00C02 ) formed by the reaction of peroxynitrite with carbon dioxide [99-102]. 

The enzyme copper, zinc superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalyzes the disproportionation of superoxide anion to dioxygen and hydrogen peroxide (equations 1 and 2). Crystallographic data can be found in References 41-46. This antioxidant enzyme is present in the cytosol and mitochondrial intermembrane space of eukaryotic cells and in the periplasmic space of bacterial cells as a homodimer of 32 kDa. Each monomer binds one copper and one zinc ion. The reaction mechanism involves the... 

The conversion of NO to HNO can proceed by several mechanisms, including formal reduction by metalloenzymes such as superoxide dismutase (SOD) (83-85) and xanthine oxidase (XO) (86) or reductants such as flavins (87) and ubiquinol (88). The reaction of 5-nitrosthiols, which would be formed initially upon NO biosynthesis, with excess thiols also releases HNO (89-92). 

Copper is an essential element to most life forms. In humans it is the third most abundant trace element only iron and zinc are present in higher quantity. Utilization of copper usually involves a protein active site which catalyzes a critical oxidation reaction, e.g., cytochrome oxidase, amine oxidases, superoxide dismutase, ferroxidases, dopamine-/ -hydrox-ylase, and tyrosinase. Accordingly, animals exhibit unique homeostatic mechanisms for the absorption, distribution, utilization, and excretion of copper (J). Moreover, at least two potentially lethal inherited diseases of copper metabolism are known Wilson s Disease and Menkes s Kinky Hair Syndrome (I). 

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